The applicant is a head and neck oncologic surgeon with overall goals of becoming an independent scientist and contributing to innovation in oral cancer treatment. This proposal serves the applicant's long term objective of improving outcomes for oral squamous cell carcinoma (OSCC) by advancing targeted therapy for aggressive, poor prognosis forms of the disease. To achieve this goal, the candidate will pursue direct laboratory-based training with close support from a team with complementary expertise in mentorship of early career clinician-scientists and his specific research areas. The plan also includes didactic and tutorial learning across diverse fields of relevance to the research plan and overall goals. These areas include pharmacology, stem cell biology, tumor microenvironment, cell signaling, epigenetics, biostatistics, and the responsible conduct of research. In addition he will actively participate in the broader cancer research community through attendance at seminars and presentation at international meetings. The proposed research plan builds upon current understanding of the epidermal growth factor receptor (EGFR) dependence in OSCC, which has led to the main targeted agent in clinical use for this malignancy, the anti-EGFR antibody cetuximab. The candidate's pursuit of combination therapies to improve the partial efficacy of EGFR targeting is guided by evidence that epithelial to mesenchymal transition (EMT) underlies key aspects of OSCC progression and cetuximab resistance. Preliminary work shows that EMT produces cellular heterogeneity within OSCCs by creating a subset of carcinoma cells with mesenchymal-like gene expression. Designated here as a mesenchymal-like subpopulation (MLSP), these cells are predicted to enhance tumor progression and express a distinct profile of secreted factors with potential impact on cetuximab resistance. The overall hypothesis is that MLSP-derived factors drive OSCC progression and cetuximab resistance through direct, tumor cell- autonomous effects and indirect effects mediated by crosstalk with stromal fibroblasts. To test this hypothesis, the proposed studies delineate the contribution of MLSP cells to OSCC growth and progression and determine both tumor cell-autonomous and fibroblast-dependent mechanisms by which they drive EGFR inhibitor resistance. In doing so, this application pursues a basis for combination therapies with cetuximab by addressing the full impact of the MLSP on the tumor microenvironment.